The present invention relates to processes for the synthesis of organic molecules, specifically molecules that have activity as thyroid receptor ligands.
While the essential role of thyroid hormones in regulating metabolism in humans is well recognized, the discovery and development of new specific drugs for improving the treatment of hyperthyroidism and hypothyroidism has been slow. This has also limited the development of thyroid agonists and antagonists for treatment of other important clinical indications, such as hypercholesterolemia, obesity and cardiac arrhythmias.
Thyroid hormones affect the metabolism of virtually every cell of the body. At normal levels, these hormones maintain body weight, the metabolic rate, body temperature, and mood, and influence serum-low density lipoprotein (LDL) levels. Thus, in hypothyroidism there is weight gain, high levels of LDL cholesterol, and depression. In excess with hyperthyroidism, these hormones lead to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmias, heart failure, muscle weakness, bone loss in postmenopausal women, and anxiety.
Thyroid hormones are currently used primarily as replacement therapy for patients with hypothyroidism. Therapy with L-thyroxine returns metabolic functions to normal and can easily be monitored with routine serum measurements of levels of thyroid-stimulating hormone (TSH), thyroxine (3,5,3xe2x80x2,5xe2x80x2-tetraiodo-L-thyronine, or T4) and triiodothyronine (3,5,3xe2x80x2-triiodo-L-thyronine, or T3). However, replacement therapy, particularly in older individuals, is limited by certain of the deleterious effects of thyroid hormones.
In addition, some effects of thyroid hormones may be therapeutically useful in non-thyroid disorders if adverse effects can be minimized or eliminated. These potentially useful influences include weight reduction, lowering of serum LDL levels, amelioration of depression and stimulation of bone formation. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism, and in particular by cardiovascular toxicity.
Development of specific and selective thyroid hormone receptor agonists could lead to specific therapies for these common disorders while avoiding the cardiovascular and other toxicities of native thyroid hormones. Tissue-selective thyroid hormone agonists may be obtained by selective tissue uptake or extrusion, topical or local delivery, targeting to cells through other ligands attached to the agonist and targeting receptor subtypes. Thyroid hormone receptor agonists that interact selectively with the xcex2-form of the thyroid hormone receptor offer an especially attractive method for avoiding cardio-toxicity.
Thyroid hormone receptors (TRs) are, like other nuclear receptors, single polypeptide chains. The various receptor forms appear to be products of two different genes xcex1 and xcex2. Further isoform differences are due to the fact that differential RNA processing results in at least two isoforms from each gene. The TRxcex11, TRxcex21 and TRxcex22 isoforms bind thyroid hormone and act as ligand-regulated transcription factors. In adults, the TRxcex21 isoform is the most prevalent form in most tissues, especially in the liver and muscle. The TRxcex11 isoform is prevalent in the pituitary and other parts of the central nervous system, does not bind thyroid hormones, and acts in many contexts as a transcriptional repressor. The TRxcex11 isoform is also widely distributed, although its levels are generally lower than those of the TRxcex21 isoform. This isoform may be especially important for development. Whereas many mutations in the TRxcex2 gene have been found and lead to the syndrome of generalized resistance to thyroid hormone, mutations leading to impaired TRxcex1 function have not been found.
A growing body of data suggest that many or most effects of thyroid hormones on the heart, and in particular on the heart rate and rhythm, are mediated through the xcex1-form of the TRxcex11 isoform, whereas most actions of the hormone such as on the liver, muscle and other tissues are mediated more through the xcex2-forms of the receptor. Thus, a TRxcex2-selective agonist might not elicit the cardiac rhythm and rate influences of the hormones but would elicit many other actions of the hormones. It is believed that the xcex1-form of the receptor is the major drive to heart rate for the following reasons:
1. tachycardia is very common in the syndrome of generalized resistance to thyroid hormone in which there are defective TRxcex2-forms, and high circulating levels of T4 and T3;
2. there was a tachycardia in the only described patient with a double deletion of the TRxcex2 gene (Takeda et al., J. Clin. Endrocrinol. and Metab. 1992, Vol. 74, p. 49);
3. a double knockout TRxcex1 gene (but not xcex2-gene) in the mouse has a slower pulse than control mice; and,
4. western blot analysis of human myocardial TRs show presence of the TRxcex11, TRxcex12 and TRxcex22 proteins, but not TRxcex21.
If these indications are correct, then a TRxcex2-selective agonist could be used to mimic a number of thyroid hormone actions, while having a lesser effect on the heart. Such a compound may be used for: (1) replacement therapy in elderly subjects with hypothyroidism who are at risk for cardiovascular complications; (2) replacement therapy in elderly subjects with subclinical hypothyroidism who are at risk for cardiovascular complications; (3) obesity; (4) hypercholesterolemia due to elevations of plasma LDL levels; (5) depression; and, (6) osteoporosis in combination with a bone resorption inhibitor.
Thyroid receptor ligands of the formula I, below, have previously been synthesized by several methods including the method summarized in Scheme A (See U.S. patent application Ser. No. 09/761,050, filed Jan. 16, 2001.) The group G represents any group appropriate for protecting a hydroxyl moiety. The group Z represents a leaving group, such as a halogen. Examples of appropriate protecting groups G can be found, for example, in T. W. Greene and P. G. M. Wuts, xe2x80x9cProtecting Groups in Organic Synthesisxe2x80x9d, 3rd Edition, Wiley, 1999. 
This route is not optimal, however, due to the exothermicity of the formation of the iodonium triflate salt which is an unisolated intermediate in the synthesis depicted in Scheme A. In addition, the isolated, bis-phenyl iodonium salt is an intractable gummy solid at room temperature, and the yield of the formation reaction is unpredictable. Further, the coupling reaction to form the mixed ether from the iodonium salt is not well adapted to commercial practice, because it takes place over an extended period of time, it requires unusual provisions to exclude light, and its yield is also unpredictable.
Accordingly, there is a need for improved processes for the preparation of thyroid receptor ligands, especially for processes that improve upon the safety and economic feasibility of the processes known in the art.
The present invention relates to the synthesis of compounds that have activity as thyroid receptor ligands, specifically compounds of formula I 
wherein:
R1 represents halogen, trifluoromethyl, an alkyl group of 1 to 6 carbons, or a cycloalkyl group of 3 to 7 carbons;
R2 and R3 are the same or different and represent hydrogen, halogen, an alkyl group of 1 to 4 carbons, or a cycloalkyl group of 3 to 6 carbons, at least one of R2 and R3 being other than hydrogen;
R4 represents hydrogen or a lower alkyl group;
R5 represents a carboxylic acid or an alkyl ester thereof; and
Y represents xe2x80x94(CH2)nxe2x80x94 where n is an integer from 1 to 5, or a cis- or trans-ethylene group xe2x80x94CHxe2x80x94CHxe2x80x94;
and all stereoisomers thereof, prodrug esters thereof, and pharmaceutically acceptable salts thereof.
Compounds of formula I may be synthesized by reacting a compound of formula III with a phenol of formula A, wherein G is a protecting group, in the presence of a base to produce a compound of formula IV, wherein R1, R2, R3, and R4 are as defined above; 
deprotecting the compound of formula IV to form a compound of formula V; 
reducing the compound of formula V to produce a compound of formula VI; 
reacting the compound of formula VI with a compound of the formula XC(O)YR5, wherein X represents OH or a halogen and R5 is a carboxylic acid alkyl ester, in the presence of a base, to produce a compound of formula I wherein R5 is a carboxylic acid alkyl ester; and
optionally de-esterifying the compound of formula I wherein R5 is a carboxylic acid alkyl ester to produce a compound of formula I wherein R5 is a carboxylic acid.
Also provided by the present invention are compounds that are novel starting materials of the above process having the formulae IIA and IIIA 
wherein
R2 and R3 independently represent bromo, chloro, or methyl;
R4 represents hydrogen or methyl; and
L represents mesyl, tosyl, p-nitrobenzenesulfonyl, trihaloacetate, or triflate.
The present invention also provides compounds of the formulae A, A-I, and A-II 
wherein M is a metal and G and R1 are as defined above. In compounds of formula A, however, when G is a methyl group, R1 is not a bromo, chloro, iodo, t-butyl, cyclohexyl, cyclopentyl, or isopropyl group.
Also provided by the present invention is a process for synthesizing a phenol of formula A, above, by reacting an aldehyde of formula A-I, above, with M+HSO3xe2x88x92 wherein M is a metal to form a sulfonate of formula A-II, above. The sulfonate of formula A-II is reacted with an oxidant in the presence of a proton source to form the phenol of formula A.